Imaging Chemotherapy-Induced Brain Damage in Pediatric Cancer Survivors Many pediatric cancer survivors face chronic and life-altering side effects as a result of their chemotherapy. Children treated with high dose methotrexate (MTX) chemotherapy can experience neurocognitive decrements that include impairments in memory, attention, and concentration. The overall cumulative incidence of neurocognitive morbidities ranges from 25 to 45%. There is a window of time between the exposure to therapy and future morbidity. Unfortunately, once cancer survivors present with clinical morbidities, it is often too late for health-preserving interventions. To prevent drug-induced clinical problems after therapy, it is important to develop diagnostic tools to detect the early stages of tissue damage that are still reversible. However, the development of related biomarkers has gained surprisingly little attention in the field. To close this gap, we aim to develop novel diagnostic biomarkers for detection of early tissue damage before clinical problems become apparent. The obtained information could then be used to initiate corrective actions before long-term morbidities occur and ultimately preserve the health of our patients. The overall goal of our project is to detect early imaging signs of chemotherapy-induced brain damage that can predict chronic neurocognitive problems months or years later. We are uniquely positioned to pursue this goal because we can leverage an image registry, which contains serial positron emission tomography (PET) and magnetic resonance imaging (MRI) scans of pediatric cancer patients before, during and after chemotherapy. Our preliminary data showed that novel PET/MRI techniques, which enable simultaneous assessment of brain morphology and metabolism, can detect and quantify physiological disturbances of the brain with high sensitivity. Using this new imaging technology, we will measure brain volume, cortical thickness (T1 SPGR), leukoencephalopathy (T2), brain perfusion (arterial spin labeling), and regional cerebral metabolic rate of glucose metabolism (rCMRglc). We hypothesize that imaging biomarkers in the dorsolateral prefrontal brain and cingulate gyrus, as measured with PET/MRI, will correlate with executive function scores, assessed with neurocognitive function tests. Prediction and early detection of MTX-induced neurotoxicity will allow us to identify patients who will benefit from early interventions, prescribe individual treatment regimes, and ultimately prevent long-term morbidities.